HDAC

Repression of genes is associated with reversal of this process under the control of histone deacetylases (HDACs). Deacetylation of histones increases the winding of DNA round histone residues, resulting in a dense chromatin structure and reduced access of transcription factors to their binding sites, thereby leading to repressed transcription of inflammatory genes. 

Histone Acetylation. Figure 1 Histone acetylation is a posttranslational modification of lysine residues of histones. This modification is catalyzed by histone actyl transferases (HATs), which transfer an acetyl group (yellow) from acetyl-Coenzyme A onto the E-amino group of the lysine residue. Histone deacetylation is catalyzed by histone deacetylases (HDACs), which hydrolyze the lysine bound acetyl group. HDAC inhibitors like Trichostatin A (TSA) are known to inhibit the deacetylation reaction in vivo and in vitro. 

The exact role of individual histone acetylations will have to be determined in the context of other modifications and the number of lysine residues effected. However, the general importance of histone acetylation as a regulator for chromatin activity is undisputed. This leads to the intriguing possibility to develop drugs that target histone acetylation for therapeutic purposes. The primary targets for drug development are the histone acetyl transferases (HATs) and the histone deacetylases (HDACs) which introduce and remove histone acetylations [2, 3]. 

Histone Deacetylases (HDACs) catalyze the removal of the acetyl groups from lysines (see Fig. 1). Together with the HATs they are responsible for maintaining the level of histone acetylation throughout the genome. The family of HDAC proteins has been divided into four classes based on phylogenetic analysis and sequence comparison. HDACs of the classes I and II share the same Zn2+-based reaction and are evolutionary related. Class IV HDACs also possess a Zn2+-based reaction... 

Like HATs, most functional HDACs are embedded in large multifunctional protein complexes, which also contain other chromatin modifying enzymes and coregulator proteins [1]. 

The HDACi s mentioned above inhibit exclusively Zn2+-dependent HDACs and not the NAD-dependent Sittuins. Researcher also focuses on development of sirtunin inhibitors and first successes like the compound siitinol have been repotted. Finally, the development of HAT inhibitors is also pursued and to date some compounds like the peptide-based inhibitor H3-CoA-20 or the small molecule MB-3 are among the first molecules to show HAT inhibition [3]. 

Gallinari P, Di Marco S, Pallaro M et al (2007) HDACS, histone deacetylation and gene transcription from molecular biology to cancer therapeutics. Cell Res 17 195-211... 

Beside coactivators so-called corepressors exist that are bound to transcription factors such as nuclear receptors and inhibit the initiation of transcription. These factors include the nuclear receptor corepressor (NCoR) and the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT), which interact with nuclear receptors and serve as platforms for complexes containing histone deacetylases (HDACs). These enzymes cause the reversal of histone acetylation of histones leading to a tightening of chromatin and enhancing its inaccessibility for RNA polymerase containing complexes. 

The core unit of the chromatin, the nucleosome, consists of histones arranged as an octamer consisting of a (H3/ H4)2-tetramer complexed with two histone H2A/H2B dimers. Accessibility to DNA-binding proteins (for replication, repair, or transcription) is achieved by posttranslational modifications of the amino-termini of the histones, the histone tails phosphorylation, acetylation, methylation, ubiquitination, and sumoyla-tion. Especially acetylation of histone tails has been linked to transcriptional activation, leading to weakened interaction of the core complexes with DNA and subsequently to decondensation of chromatin. In contrast, deacetylation leads to transcriptional repression. As mentioned above, transcriptional coactivators either possess HAT activity or recruit HATs. HDACs in turn act as corepressors. 

Fig. 3.16 Dynamic model for polyamide intervention in LSF2/YYI induction of latency. The host factor LSF (orange oval) is shown bound to the HiV long terminal repeat (LTR) and recruits YYl (green triangle) followed by HDAC...

Interestingly, post integration latency in microglial cells seems to be the result of the concerted action of both HDACs as well as HMTs on core histone H3 in nuc-1 (Marban et al. 2007). COUP-TF interacting protein 2 (CTIP2), a transcriptional repressor interacts with HDACl and HDAC2 via its N-terminus to repress... 

WUliams SA, Chen LE, Kwon H, Ruiz-Jarabo CM, Verdin E, Greene WC (2006) NF-kappaB p50 promotes HIV latency through HDAC recruitment and repression of transcriptional initiation. EMBO J 25(1) 139-149... 

Cylarabine (Ara-C cytosine arabinoside Cytosar U)d ANLL ALL Lymphomatous meningitis NHL MDS High-dose ara-C (HDAC) liposomal cytarabine (Depocyt) for intrathecal use for lymphomatous meningitis... 

HDAC toxicides cerebellar direct neurotoxicity ataxia, slurred speech, nystagmus conjunctivitis (drug is excreted into tears and blocks corneal DNA synthesis)... 

Before our work [39], only one catalytic mechanism for zinc dependent HDACs has been proposed in the literature, which was originated from the crystallographic study of HDLP [47], a histone-deacetylase-like protein that is widely used as a model for class-I HDACs. In the enzyme active site, the catalytic metal zinc is penta-coordinated by two asp residues, one histidine residues as well as the inhibitor [47], Based on their crystal structures, Finnin et al. [47] postulated a catalytic mechanism for HDACs in which the first reaction step is analogous to the hydroxide mechanism for zinc proteases zinc-bound water is a nucleophile and Zn2+ is five-fold coordinated during the reaction process. However, recent experimental studies by Kapustin et al. suggested that the transition state of HDACs may not be analogous to zinc-proteases [48], which cast some doubts on this mechanism. 

In addition to histone deacetylation, histone lysine methylation can also lead to gene silencing which is not blocked by the HDAC inhibitors [6, 51], Several lines of evidence have suggested a connection between cancer and histone lysine methyltrans-ferases (HKMTs) [52], HKMTs catalyze the transfer of methyl group(s) from the cofactor. S -adenosyI-methionine (AdoMet) to some specific lysine residues in the N-terminal histone tails [53, 54], With one exception of Dotl [55], all known HKMTs contain the SET domain which represents a novel structural fold [53, 56], Among SET-domain HKMTs, SET7/9 is one of the best characterized experimentally. It is a... 

De ruijter AJM, Vangennip AH, Caron HN, Kemp S, Vankuilenburg ABP (2003) Histone deacety-lases (hdacs) characterization of the classical hdac family. Biochem J 370 737-749... 

Figure 1 Structures of traditional HDAC inhibitors 1-3 and HDAC inhibitors now in clinical trials (4-8).

A series of aryltriazolylhydroxamates were reported as histone deacetylase (HDAC) inhibitors, exemplified by 49 (HDAC IC50 = 9.6 nM) which exhibited activity (L.d. IC50 = 4.5 pg/ mL) in an in vitro antileishmanial assay [48]. 

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